2012
DOI: 10.1016/j.celrep.2012.03.010
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Abstract: Summary Mice deficient in caspase-8, FADD, or cFLIP, present defects in yolk sac vascularization and embryonic lethality at E10.5. Ablation of RIPK3, a kinase that promotes a form of necrotic cell death, has recently been shown to rescue embryonic lethality in caspase-8 deficient animals. Here we show that while FADD, RIPK3 double knockouts develop normally, the lethal effects of cFLIP deletion are not rescued by RIPK3 deficiency. Remarkably, embryos lacking FADD, cFLIP, and RIPK3 develop normally. Distinct re… Show more

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Cited by 282 publications
(244 citation statements)
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“…51,54,98,99 Deletion of c-Flip causes embryonic lethality with blood vessel abnormality similar to deletion of caspase-8 or of Tak1 (Table 1). 98 Thus far, two mechanisms for caspase-c-FLIP inhibition of necroptosis are proposed: one is that caspase-8-c-FLIP cleaves and degrades RIPK1 and RIPK3; 100,101 and the other is that caspase-8 cleaves and degrades a deubiquitinase CYLD, resulting in stabilization of the polyubiquitin chain of RIPK1, which prevents RIPK3 activation. 76 In contrast to caspase-8-c-FLIP regulation of necroptosis, the regulation of apoptosis by necroptosis signaling proteins is just beginning to be investigated.…”
Section: Tak1mentioning
confidence: 99%
“…51,54,98,99 Deletion of c-Flip causes embryonic lethality with blood vessel abnormality similar to deletion of caspase-8 or of Tak1 (Table 1). 98 Thus far, two mechanisms for caspase-c-FLIP inhibition of necroptosis are proposed: one is that caspase-8-c-FLIP cleaves and degrades RIPK1 and RIPK3; 100,101 and the other is that caspase-8 cleaves and degrades a deubiquitinase CYLD, resulting in stabilization of the polyubiquitin chain of RIPK1, which prevents RIPK3 activation. 76 In contrast to caspase-8-c-FLIP regulation of necroptosis, the regulation of apoptosis by necroptosis signaling proteins is just beginning to be investigated.…”
Section: Tak1mentioning
confidence: 99%
“…66 Caspase 8 has also been shown to repress necrosis by processing CYLD. 67 Interestingly, caspase 8 appears to act in a proteolytically active complex with FADD and cFLIP to block RIP1-and RIP3-mediated necrosis, 65,68 with c-FLIP- 69 and FADD-70,71 deficient cells being highly sensitive to death by necrosis. This is consistent with the developmental lethality, due to cardiac failure, in FADDdeficient embryos, 72 with RIP1 deficiency rescuing the embryonic lethality associated with FADD deficiency.…”
Section: Rip1 and Rip3 As Drivers Of Necroptosismentioning
confidence: 99%
“…Interestingly, cFLIP deficiency is also lethal (Yeh et al 2000). This lethality could only be reversed by concomitant deficiency in RIP3 and FADD but not when either factor was absent individually (Dillon et al 2012). Thus, cFLIP is required for caspase-8 and FADD to block RIP1/ RIP3-induced lethality (van Raam and Salvesen 2012), but also to interfere with caspase-8-induced lethality.…”
Section: Complex II Of Tnf-r1 Signaling: Cell Death In Two Flavorsmentioning
confidence: 99%